Process for the synthesis of a propargylic alcohol

ABSTRACT

A process for the preparation of the compound of formula

This application is the U.S. National Phase of, and Applicants claimpriority from, International Application Number PCT/EP2010/002225 filedApr. 9, 2010, U.S. Provisional Patent Application bearing Ser. No.61/167,908 filed Apr. 9, 2009 and European Patent Application No.09005215.0 filed on Apr. 9, 2009, which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

The invention is directed to a process for the preparation of thecompound of formula,

i.e.2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-4-cyclopropyl-but-3-yn-2-ol(SD573). This compound is an important intermediate for the preparationof(−)-6-chloro-4-(cyclopropyl-ethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,which is a potent reverse transcriptase inhibitor for the treatment ofHI viruses.

Jiang et al. disclosed in Tetrahedron Lett. 2002, 43, 8323-8325 and J.Org. Chem. 2002, 67, 9449-9451 the reaction of acetylene derivativeswith aldehydes and ketones in the presence of equimolar amounts of azinc(II) compound to give several racemic propargylic alcohols. Chiralcompounds are not mentioned at all.

WO-A-95/20389, WO-A-96/37457, WO 98/30543 and WO 98/30540 discloseseveral processes for the production of chiral propargylic alcoholsuseful for the synthesis of pharmaceuticals. WO-A-98/51676 discloses aprocess wherein by addition of a first chiral and optionally a secondadditive in a zinc(II) mediated reaction the chiral product is obtainedin high enantiomeric excess. The disadvantage of said process is the useof high amounts of expensive zinc catalysts and chiral compounds.

WO-A-2004/87628 further discloses facultative use of a chiral auxiliaryin an equivalent molar amount in respect of the zinc(II) compound forthe production of chiral propargylic alcohols mentioned above.

A main problem to be solved was therefore to supply an alternativeprocess for the production of DMP266. A further problem was to reducethe amounts of catalyst and other components to be added during thereaction, in order to facilitate the workup procedures of the productand to promote industrial production.

DESCRIPTION OF THE INVENTION

The problem is solved by the process of claim 1. The inventive processcomprises the addition of the product to the reaction mixture as achiral mediator, which allows to reduce the amount of further chiralauxiliaries. Presence of the chiral product from the beginning of thereaction has the advantageous side effect that the amount of thezinc(II) catalyst can be reduced compared to processes known in the art.Furthermore, the addition of the compound of formula I allows todispense with chiral auxiliaries, while still the chiral product isformed in high enantiomeric excess (ee).

Claimed is a process for the preparation of the compound of formula

said process comprising the steps of(i) preparing a mixture of a zinc(II) catalyst, an initial amount of thecompound of formula I in a molar ratio to the zinc(II) catalyst from0.1:1 to 2:1, and optionally a chiral auxiliary in a molar ratio to thezinc(II) catalyst from 0.1:1 to 3:1, and(ii) adding to said mixture(a) the compound of formula

(b) a base, and(c) the compound of formula

at a mixing temperature from −78 to 30° C., and(iii) heating the mixture obtained in step (ii) to 10 to 50° C. untilcompletion of the reaction, to obtain the compound of formula I.

Regarding the addition of compounds in step (ii) the inventive processdoes not rely on a specific order of addition. In a preferred embodimentthe compounds of formula II and the base are added simultaneously,either separately or as a mixture. The compound of formula II may alsobe added before or after the addition of compound formula III or bothcompounds may added simultaneously, either separately or as a mixture.In the latter case preferably the compound of formula II is fed togetherwith the base.

The process is designed to obtain the compound of formula I with anenantiomeric excess (ee) of at least 60%, preferably with an ee of atleast 70%, more preferred of at least 80%, and even more preferred of atleast 90%.

In a preferred embodiment the reaction is carried out in the presence ofa proton source selected from the group consisting of C₁₋₆-alcohols,phenols, benzyl alcohols, and linear or branched C₂₋₅-alkanoic acids,each of said C₁₋₆-alcohol, phenol and benzyl alcohol optionally beingsubstituted with one or more halogen atoms, nitro, methyl or arylgroups, said C₂₋₅-alkanoic acid optionally being substituted with one ormore halogen atoms. Both, the alcohol and the acid facilitate the protonexchange. Especially the addition of the acid is not intended to changethe pH of the solution. The alcohol and the acid may be added at anytime before completion of the reaction.

Preferably the zinc(II) catalyst is used in the process in a total molarratio to the compound of formula II from 0.1:1 to 0.3:1. By using theproduct itself as the main chiral auxiliary the amount of the zinc(II)catalyst needed in the reaction can be reduced remarkably compared toprocesses known in the art. The compound of formula I mediates thecatalytic process and although the zinc(II) catalyst and the compound offormula I form a zinc(II) complex with a certain stoichiometry it is notnecessary to add the chiral compound of formula I and the zinc(II)catalyst in the same molar amount. Preferably the amount of theinitially added compound of formula I is higher than the amount of thezinc(II) catalyst.

Suitable zinc(II) catalysts are for example di(C₁₋₄-alkyl)zinc,diphenylzinc, Zn(OTf)₂ and ZnCl₂, wherein the alkyl moieties areindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tent-butyl. OTfdenotes a triflate (trifluoromethanesulfonate) group.

In a preferred embodiment the compound of formula I used as an auxiliaryin step (i) is added in a molar ratio to the compound of formula IIIfrom 0.1:1 to 0.45:1. The compound of formula I and the zinc(II)catalyst are part of an chiral zinc(II) complex mediating anautocatalytic process. Autocatalysis in the present Zn(II) mediatedautocatalytic process has the meaning that a chiral zinc(II) complexpromotes the reaction in such a way, that the reaction may carried outin the absence of any further chiral auxiliary. Chiral compounds offormula I for use as initial amount may be obtained by production ofracemic compounds and subsequent chiral resolution. Although saidzinc(II) complex has a certain stoichiometry it is not necessary to addthe chiral compound of formula I, or any optionally further auxiliary,and the Zn(II) catalyst in equimolar amounts.

In a preferred embodiment the compound of formula I used as a auxiliaryin step (i) is added in a molar ratio to the compound of formula IIIfrom 0.1:1 to 0.45:1.

A chiral auxiliary may be used to increase the meditative effect of thecompound of formula Ito give the desired enantiomer of formula I.Preferably the auxiliary is selected from the group consisting of[R—(R,S)]-β-methyl-α-phenyl-1-pyrrolidineethanol((1R,2S)-pyrrolidinylnorephedrine=(1R,2S)-PNE), N-methylephedrine,ephedrine, N,N-dibenzoylephedrine, norephedrine, diethyl tartate,(1R,2R)-pseudoephedrine, cinchonine, (1S,2S)—N-methylpseudoephedrine,2-(pyrrolidin-1-yl)ethanol, and N,N-dibutyl-2-amino-ethnol. (1R,2S)-PNEis a preferred auxiliary.

In a preferred embodiment in step (ii) the compound of formula II isused in a molar ratio to the compound of formula III from 0.8:1 to 3:1.

Addition of the compound of formula III can be carried out at atemperature from −78 to +30° C.

In a preferred embodiment the compounds of formula II are selected fromthe group consisting of p-methylbenzaldehyde, p-fluorobenzaldehyde,p-cyanobenzaldehyde, p-methoxybenzaldehyde, naphthalenealdehyde,cinnamaldehyde, C₃₋₂₀-alkane aldehydes, cycloheane carbaldehyde,cyclohexyl metyl ketone, methyl 4-metylcyclohexyl ketone,1,1,1-trifluoroacetophenone and 2-(trifluoroaceto)-4-chloro-anilin.

In a further preferred embodiment of step (ii), the base is added in amolar ratio to the compound of formula III from 0.5:1 to 3:1.

Addition of the base can be carried out at a temperature from −40 to+10° C. In a preferred embodiment the compounds of formula III areselected from the group consisting of C₁₋₆-alkane acetylenes,cyclopropylacetylene, (1′-methyl)-cyclopropyl-acetylene andphenylacetylene.

A suitable base for the present process is a strong base such as sodiumhydroxide, potassium hydroxide, caesium hydroxide, sodium hydride,potassium hydride, trimethylamine, triethylamine, potassiumtrimethylsilanolate, lithium trimethylsilanolate, lithiumtert-butoxylate, lithium 2,2,2-trifluoroethoxylate, butyllithium andhexyllithium.

Preferably said base is an organometallic compound or a lithium organicsalt.

In a preferred embodiment such organo lithium compound is selected fromthe group consisting of phenyllithium and (C₁₋₆-alkyl) lithium, such asmethyllithium, ethyllithium, n-propyllithium, n-butyllithium (BuLi),n-hexyllithium (HexLi) or n-octyllithium.

In a further preferred embodiment the lithium organic salt is a lithiumC₁₋₆-alkoxide.

Expediently, an organometallic lithium compound or lithium organic saltis used in the presence of a Lewis base or a nitrogen ligand such asdiethyl ether, tetrahydrofuran (THF), tetramethylenediamine (TMEDA),N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDTA), or a sparteine suchas (−)-sparteine, to deaggregate the lithium compound.

During the addition of the base the reaction mixture is preferably keptat a temperature from −40 to +10° C.

The inventive process may be carried out with or without solvent. In apreferred embodiment the process is carried out in an aprotic polar, anon-polar solvent or a mixture of aprotic polar and/or non-polarsolvents.

The solvents of agents added in solution may be selected independentlyof each other. Particularly preferred the solvent is selected from thegroup consisting of Tetrahydrofuran (THF), benzene, chlorobenzene, o-,m-, p-dichlorobenzene, dichloromethane, toluene, hexanes, cyclohexane,pentane, 1,4-dioxane, cyclohexane, diethyl ether, tert-butyl methylether, diisopropyl ether, N-methylpyrrolidine, or a mixture thereof.

Here and hereinbelow the term “alkyl” represents a linear or branchedalkyl group. By using the form “C_(1-n)-alkyl” the alkyl group is meanthaving 1 to n carbon atoms. C₁₋₈-alkyl represents for example methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, aswell as linear and branched pentyl, hexyl, heptyl and octyl.

Here and hereinbelow the term “alkoxy” represents a linear or branchedalkoxy group. By using the form “C_(1-n)-alkoxy” the alkyl group ismeant having 1 to n carbon atoms. C₁₋₆-alkoxy represents for examplemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tent-butoxy, as well as linear and branched pentyloxy and hexyloxy.

Here and hereinbelow the term “aryl” represents an aromatic group,preferably phenyl or naphthyl.

If a C₁₋₆-alcohol is added as a proton source said C₁₋₆-alcohol isselected from the group consisting of methanol, ethanol, propanol,isopropyl alcohol, butanol, isobanol, sec-butanol, tent-butanol,pentanol, (CH₃)₃CCH₂OH, (CH₃)₃CCH(CH₃)OH, Cl₃CCH₂OH, CF₃CH₂OH,CH₂═CHCH₂OH, (CH₃)₂NCH₂CH₂OH. Examples for suitable benzyl alcohols andphenols are phenol, PhCH₂OH, Ph₃COH, 4-Cl-phenol and 4-NO₂-phenol.

In a further preferred embodiment a C₂₋₅-alkanoic acid added as a protonsource is selected from the group consisting of acetic acid, proponicacid, butyric acid, CF₃CO₂H, CH₃CHClCOOH and (CH₃)₃CCO₂H.

EXAMPLES

For calculation of the yield of the product, as well as for thecalculation of the enantiomeric excess the product added in step (i) ofthe process is subtracted.

Example 1

Procedure for the autocatalytic formation of(S)-5-chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol(SD573 or (S)-2): A reaction flask, equipped with thermometer,mechanical stirrer, N₂ outlet and 2 dropping funnels, is dried andflushed with nitrogen. The flask is charged with(1R,2S)—N-pyrrolidinylnorephedrine ((1S,2R)-PNE, 17.2% in THF/toluene atapprox. 90:10 (w/w), 0.3 eq, 75 mmol) and the compound of formula I(SD573, 0.18 eq, 45 mmol). A solution of diethyl zinc(II) (DEZ, 0.24 eq,1.1 M in toluene, 60 mmol) is dropwise added to the mixture of[R—(R,S)]-β-methyl-α-phenyl-1-pyrrolidineethanol ((1R,2S)-PNE) and SD573at 17° C., followed by 30 min of stirring at r.t. Cyclopropylacetylene(2 eq, 70.4% in toluene, 500 mmol) is added dropwise at a reactiontemperature 15° C. and the mixture is stirred for additional 1.5 h atr.t. 2-Trifluoromethylcarbonyl-4-chloroaniline (SD570, a ketoaniline offormula II) (40.4% in THF/toluene, 1 eq, 250 mmol) is addedsimultaneously with hexyllithium (HexLi, 0.9 eq, 2.3 M in hexane, 225mmol) at 0° C. to 1.8° C. within 7 h, by means of the two droppingfunnels. The rate of the addition is kept as equal as possible for bothreagents. At the completion of SD570 and base addition, 3 mL ofanhydrous THF are added to wash down the leftovers of SD570 whichcrystallized on the edge of the funnel outlet. The reaction mixture isstirred at r.t. for 2 h, followed by heating to 40° C. A first aliquotwas withdrawn after 2 h of heating and a second aliquot was withdrawnafter 12 hours of heating. 0.5 mL of each aliquot is quenched withcitric acid to pH=4 to 5, diluted by EtOAc, the organic phase is driedover MgSO₄, filtrated and submitted to the HPLC analysis(Hex/iPrOH=85:15 (w/w), chiralpack, AD-H, 25×4.6, flow=1 mL/min). Thereaction affords the compound of formula I (SD573). 2 h aliquot:Enantiomeric excess (ee)=97.16%, conversion (Con.)=98.04%, selectivity(Sel.)=97%. 12 h aliquot: ee=97.03%, Con.=99.05%, Sel.=97.45%. Unlessotherwise indicated the ee values in all examples have been correctedregarding the initial amount of the compound of formula I.

Example 2

Reaction according to example 1 but using only one equivalent (1.0 eq.)of Cyclopropyl-acetylene compared to the compound of formula II affordedthe compound of formula I after 5 h reaction time at 40° C.: ee=89.3%,Con.=90%, Sel.=70.8%.

Example 3

Reaction according to example 1 but using racemic PNE as auxiliaryafforded the compound of formula I after different reaction times at 40°C.: after 3 h: ee=64.6%, Con.=79.4%, Sel.=81.4%; after 4 h: Con.=80.6%,Sel.=87.1%; after 22 h: ee=68%, Con.=96%, Sel.=76.6%.

Example 4

Reaction according to example 1 but using 2-(N,N-dibutyl)-amino ethanol(DBAE) as auxiliary and maintaining the reaction mixture 12 h at r.t.after addition of the base before heating to 40° C., afforded thecompound of formula I after different reaction times at 40° C.: 3 haliquot: ee=64%, C=90.6%, S=71.4%; 5 h aliquot: ee=60%, C=85.6%,S=70.3%.

Example 5

Reaction according to example 4 but maintaining the reaction mixture 8 hat r.t. after addition of the base before heating to 30° C., affordedthe compound of formula I: 0 h aliquot (before heating): ee=78%,Con.=35.2%, Sel.=84%; and at different reaction times at 30° C.: 2 haliquot: ee=65.3%, Con.=80%, Sel.=54.4%; 22 h: ee=56.6%, Con.=94.6%,Sel.=61.2%.

The invention claimed is:
 1. A process for the preparation of a chiralcompound of formula

said process comprising the steps of (i) preparing a mixture of azinc(II) catalyst, a starting amount of the compound of formula I in amolar ratio to the zinc(II) catalyst from 0.1:1 to 2:1, and optionally achiral auxiliary in a molar ratio to the zinc(II) catalyst of 0.1:1 to3:1, and (ii) adding to said mixture (a) the compound of formula

(b) a base (c) the compound of formula

at a mixing temperature from −78 to 30° C., and (iii) heating themixture obtained in step (ii) to 10 to 50° C. until completion of thereaction.
 2. The process of claim 1, wherein the process is carried outin the presence of a proton source selected from the group consisting ofC₁₋₆-alcohols, benzyl alcohols, phenols and linear or branchedC₂₋₅-alkanoic acids, each of said C₁₋₆-alcohol, phenol and benzylalcohol optionally being substituted with one or more substituentselected from the group consisting of halogen atoms, nitro, methyl andaryl groups, said C₂₋₅-alkanoic acid optionally being substituted withone or more substituent selected from the group consisting of halogenatoms.
 3. The process of claim 1, wherein the zinc(II) catalyst is usedin a total molar ratio to the compound of formula II from 0.1:1 to0.3:1.
 4. The process of claim 1, wherein the zinc(II) catalyst isselected from the group consisting of di(C₁₋₄-alkyl)zinc, diphenylzinc,Zn(OTf)₂ and ZnCl₂, wherein the alkyl moieties are independentlyselected from the group consisting of methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl.
 5. The process of claim 1,wherein in step (i) the product of formula I is added in a molar ratioto the compound of formula III from 0.1:1 to 0.45:1.
 6. The process ofclaim 1, wherein in step (ii) the compound of formula II is used in amolar ratio to the compound of formula III from 0.8:1 to 3:1.
 7. Theprocess of claim 1, wherein the base is added in a molar ratio to thecompound of formula III from 0.5:1 to 3:1.
 8. The process of claim 1,wherein the base is an organometallic compound or a lithium organicsalt.
 9. The process of claim 8, wherein the organometallic compound isselected from the group consisting of phenyllithium or (C₁₋₈-alkyl)lithium.
 10. The process of claim 8, wherein the lithium organic salt isa lithium C₁₋₆-alkoxide.
 11. The process of claim 1, wherein thetemperature during the addition of the base is of from −40 to +10° C.12. The process of claim 1, wherein the reaction is carried out in anaprotic polar or non-polar solvent or a mixture of aprotic polar and/ornon-polar solvents.